One of the most well-known and widely used class of antibacterial agents are the so-called .beta.-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (.beta.-lactam) ring fused to either a thiazolidine or a dihydro-1,3-thiazine ring. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the .beta.-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given .beta.-lactam antibiotic results because the microorganism produces a .beta.-lactamase. The latter substances are enzymes which cleave the .beta.-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit .beta.-lactamases, and when a .beta.-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a .beta.-lactamase inhibiting substance and a .beta.-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components.
The present invention relates to a series of 6-.beta.-substituted penicillanic acids and readily hydrolyzable in vivo esters thereof which are potent inhibitors of microbial .beta.-lactamases and enhance the effectiveness of .beta.-lactam antibiotics. The invention further relates to 6-.beta.-substituted penicillanic acid esters wherein said ester portion is a penicillin carboxy protecting group, said esters being useful chemical intermediates to the corresponding acids.
The invention also relates to a process for the preparation of the 6-.beta.-substituted penicillanic acids, their readily hydrolyzable in vivo esters and esters thereof wherein said ester portion is a penicillin carboxy protecting group.
Pharmaceutical compositions comprising the above-mentioned 6-.beta.-substituted penicillanic acids and hydrolyzable esters with certain .beta.-lactam antibiotics as well as a method for increasing the effectiveness of certain .beta.-lactam antibiotics in combination with the above-mentioned 6-.beta.-substituted penicillanic acids and hydrolyzable esters are also parts of the present invention.
6-Substituted penicillanic acids and certain esters have been prepared through 6-diazopenicillanic acid (Helv. Chim. Acta., 50, 1327 (1967), but the orientation of the substituent is in the .alpha.-position. 6-.alpha.-Hydroxy-penicillanic acid is also prepared from 6-diazopenicillanic acid and esters thereof (J. Org. Chem., 39, 1444 (1974).
6-.alpha.-Benzyloxypenicillanic acid methyl ester is reported by Manhas, et al., J. Heterocycl. Chem., 15. 601 (1978).
Certain 6,6-dihalo- and 6-halopenicillanic acids are reported by Harrision, et al., J. Chem. Soc., 1772 (1977). In each instance of a mono substituted penicillanic acid the 6-.alpha. epimer is described.
More recently Loosemore, et al., J. Org. Chem., 43, 3611 (1978) reported that treatment of a 6-.alpha.-bromopenicillanic acid with base epimerized a portion of the compound to give a mixture of 6-.alpha.- and 6-.beta.-bromopenicillanic acid which was comprised of about 12% of the .beta.-epimer. A similar mixture was achieved through a hydrogenation of 6,6-dibromopenicillanic acid in which the .beta.-epimer comprised about 30% of the total. It was also shown by Pratt, et al., Proc. Natl. Acad. Sci., 75, 4145 (1978) that the .beta.-lactamase inhibitory characteristic of a mixture of 6-.alpha.- and 6-.beta.-bromopenicillanic acid was related to the amount of 6-.beta.-bromopenicillanic acid in said mixture. The findings of Pratt, et al., are corroborated by Knott-Hunziker, et al., Biochem, J., 177, 365 (1979) by the demonstration that a mixture of 5% 6-.beta.-bromopenicillanic acid and 95% 6-.alpha.-bromopenicillanic acid inhibits .beta.-lactamase while the .alpha.-epimer alone is essentially inactive.
U.S. Pat. No. 4,093,625 claims the preparation of 6-.beta.-mercaptopenicillanic acid and derivatives thereof as antibacterial agents.
Cartwright et al., Nature 278, 360 (1979) reports that while 6.alpha.-chloropenicillanic is a poor inhibitor of .beta.-lactamase, the corresponding sulfone is a moderately good inhibitor.
Roets, et al., J. Chem. Soc., (Perkin I) 704 (1976) identifies benzyl 6.beta.-chloropenicillanate as a by-product in the reduction of benzyl 6-oxopenicillanate following hydrochloric acid treatment of the product.
Recently John, et al., J. Chem. Soc. Chem. Comm., 345 (1979) reported the preparation of benzyl 6.beta.-bromopenicillanate from benzyl 6,6-dibromopenicllanate using a tin hydride reduction.